EP4089087A1 - Verfahren zur herstellung von pyrrolidinylharnstoffderivaten - Google Patents

Verfahren zur herstellung von pyrrolidinylharnstoffderivaten Download PDF

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Publication number
EP4089087A1
EP4089087A1 EP21738162.3A EP21738162A EP4089087A1 EP 4089087 A1 EP4089087 A1 EP 4089087A1 EP 21738162 A EP21738162 A EP 21738162A EP 4089087 A1 EP4089087 A1 EP 4089087A1
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EP
European Patent Office
Prior art keywords
compound
reagent
reaction system
solvent
tetrahydrofuran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP21738162.3A
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English (en)
French (fr)
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EP4089087B1 (de
EP4089087A4 (de
Inventor
Jinming Huang
Juan Yu
Jinxiang ZENG
Limei YANG
Tingting YIN
Yang Zhang
Wentao Wu
Zhixiang LI
Jian Qin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhangzhou Pientzehuang Pharmaceutical Co Ltd
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Zhangzhou Pientzehuang Pharmaceutical Co Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure relates to a method for preparing a pyrrolidinyl urea derivative as a TrkA inhibitor, and also relates to an intermediate compound of compound represented by formula (I) and a preparation method thereof.
  • Tropomyosin-related kinase is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor (NT), whose family consists of three members (TrkA, TrkB, TrkC).
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT neurotrophic factor
  • family consists of three members (TrkA, TrkB, TrkC).
  • NGF, BDNF and NT-4/5 play an important role in many physiological regulation processes such as signal maintenance, signal transmission, cell proliferation, cell differentiation and cell survival of neuronal cells through receptor Trk.
  • TrkA inhibitors of the present disclosure can solve the treatment needs of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • WO2015175788 patent reported a single compound with inhibitory activity against TrkA and a pharmaceutically acceptable salt thereof.
  • WO2012158413 , WO2016116900 , WO2016021629 and WO2017006953 have reported a series of compounds with inhibitory activity against TrkA, including the pyrrolidinyl urea structure used in the present disclosure.
  • the present disclosure provides a method for preparing compound represented by formula (I), comprising the following steps:
  • the method comprises the following reaction route: wherein,
  • the temperature range of the reaction system is controlled to be 65 ⁇ 5°C.
  • the molar ratio of compound SM3-9 to compound SM3-10 is 1:1.2 to 2.
  • the molar ratio of compound SM1 to catalyst U is 1:0.05 to 0.1.
  • the temperature range of the reaction system is controlled to be 0 ⁇ 5°C.
  • the molar ratio of compound SM3-3 to reagent C is 1:12 to 17.
  • the temperature range of the reaction system is controlled to be 0 ⁇ 5°C.
  • the molar ratio of compound SM3-5 to reducing reagent F is 1:2 to 4.
  • the temperature range of the reaction system is controlled to be 15 ⁇ 5°C.
  • the temperature range of the reaction system is controlled to be 20 ⁇ 5°C.
  • the reaction system in the method, wherein, in the step of preparing compound SM3-7, after the completion of the reaction, the reaction system is kept under nitrogen atmosphere for filtration.
  • the temperature range of the reaction system is controlled to be 80 ⁇ 5°C.
  • the pH is adjusted with acid and controlled at 2.7 to 3.5 in the post-treatment.
  • the temperature range of the reaction system is controlled to be 35 ⁇ 5°C when adjusting the pH in post-treatment.
  • the molar ratio of compound SM3-8 to reagent N is 1:1.5 to 2.
  • the molar ratio of compound SM3-11 to reagent Q is 1:2.5 to 4.
  • the temperature range of the reaction system is controlled to be 5 ⁇ 5°C.
  • the reaction time is 1.5 ⁇ 0.5 hours.
  • the molar ratio of compound 1-4 to base Y is 1:5.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred implementations include but are not limited to the embodiments of the present disclosure.
  • the structure of the compounds of the present disclosure can be confirmed by conventional methods known to those skilled in the art, and if the disclosure involves an absolute configuration of a compound, then the absolute configuration can be confirmed by means of conventional techniques in the art.
  • the absolute configuration can be confirmed by collecting diffraction intensity data from the cultured single crystal using a Bruker D8 venture diffractometer with CuK ⁇ radiation as the light source and scanning mode: ⁇ / ⁇ scan, and after collecting the relevant data, the crystal structure can be further analyzed by direct method (Shelxs97).
  • the compounds of the present disclosure are named according to the conventional naming principles in the art or by ChemDraw ® software, and the commercially available compounds use the supplier catalog names.
  • the process for synthesizing the compound of formula (I) and intermediates thereof provided by the present disclosure has the beneficial effects of cheap and easy-to-obtain raw materials, overcoming shortcomings such as difficulty in separation and purification and difficulty in industrialization, and avoiding the steps that are not suitable for scale-up production such as the state-regulated highly toxic methanesulfonyl chloride, hydrogenation reduction reaction of flammable and explosive sodium azide and palladium carbon, the total synthesis route is shortened, waste discharge is reduced, and more economical and practical.
  • the present disclosure has high industrial application value and economic value in the preparation of the compound of formula (I) and the intermediate thereof.
  • step 1
  • step 2
  • diethylaminosulfur trifluoride (32.54 g, 2.68 mol, 354.54 mL, 1.55 eq) was dissolved in anhydrous dichloromethane (600 mL), and a solution of compound SM1-2 (400 g, 1.73 mol, 1 eq) in anhydrous dichloromethane (2000 mL) was added dropwise. After the completion of dropwise addition, the reaction solution was slowly warmed to 25°C and stirred for one hour.
  • 1 HNMR 400 MHz, CDCl 3 ): 8.891 (s, 2H), 5.18 - 5.05 (m, 4H).
  • step 3
  • step 4
  • step 5
  • step 6
  • step 7
  • step 8
  • step 9
  • reaction solution was cooled to 20 to 30 °C, sodium sulfate decahydrate (284 g, 1.32 mol, 1 eq), water (284 mL) and 20% aqueous sodium hydroxide solution (284 mL) were sequentially added, and the reaction solution was warmed to 60 °C and continued stirring for one hour.
  • the reaction solution was filtrated, the filter cake was washed twice with 4000 mL of tetrahydrofuran, the obtained filter cake was added to 4000 mL of tetrahydrofuran and 500 mL of 20% aqueous sodium hydroxide solution, 500 g of anhydrous sodium sulfate was added, the mixture was filtered, the organic phases were combined, and 41 batches the organic phases were combined, the organic phase was removed under reduced pressure to obtain 4.34 kg of compound SM3-6 (content: 83%, yield: 41.2%).
  • step 10
  • sulfonic acid isocyanate (614.6 g, 4.34 mol, 3.5 eq) was dissolved in anhydrous 1,4-dioxane (800 mL), the reaction solution was cooled to 10 to 20 °C, and a solution of tert-butanol (321.9 g, 4.34 mol, 3.5 eq) in 1,4-dioxane (600 mL) was slowly added, the internal temperature was kept at 10 to 20 °C, and the mixture was continued stirring for 0.5 hours after the dropwise addition, and the obtained solution was used for later use.
  • reaction solution was filtrated under nitrogen protection, the filter cake was washed once with anhydrous dioxane, triethylamine (213 g, 2.1 mol, 1.7 eq) was added to the filtrate, and the reaction solution was warmed to 82 °C and continued stirring for 4 hours.
  • step 11
  • the temperature of the reaction was cooled down, and the reaction solution was filtered through diatomite, and the organic solvent was removed under reduced pressure, the obtained residue was dissolved in 2000 mL of tetrahydrofuran, the pH was adjusted to 2.7 to 3.5 with 0.5 M aqueous hydrochloric acid solution, and the reaction solution was warmed to 40 °C and continued stirring for one hour.
  • step 12
  • step 13
  • step 14
  • step 15
  • step 16
  • step 17
  • reaction solution was cooled to room temperature, filtered through diatomite, the filter cake was washed with ethyl acetate (5 L), the combined filtrate was added with saturated brine (10 L) for separation, and the aqueous phase was extracted with ethyl acetate (10 L ⁇ 2), the combined organic phase was concentrated under reduced pressure to 30L, activated carbon (2.0 kg), anhydrous magnesium sulfate (4.0 kg) and metal scavenger (3-mercaptopropyl functional silica gel, 2.0 kg) were added, and the temperature was warmed to 55 °C and continued stirring for 18 hours, the reaction solution was filtered through diatomite, the filter cake was washed with ethyl acetate (10 L ⁇ 2), the organic solvent was removed under reduced pressure, and the crude product was added to methyl tert-butyl ether (5 L), n-heptane (1 L) was added and continued stirring at room temperature for 15 to 18 hours, filtered, the filter cake was washed with
  • step 18
  • compound 1-2 (0.73 kg, 2.24 mol, 1 eq) was dissolved in anhydrous dichloromethane (15 L), pyridine (0.54 kg, 6.74 mol, 3 eq) was added, the mixture was cooled to 0 °C, and a solution of compound 1-3 (0.46 kg, 2.92 mol,1.3 eq) in dichloromethane (1.2 L) was added dropwise, and the internal temperature of the reaction solution was kept below 10 °C, after the completion of the dropwise addition, the reaction solution was continued stirring at this temperature for 0.5 to 2 hours.
  • step 19
  • reaction solution was added to water (6.0 L) and ethyl acetate (6.0 L) to partition, the aqueous phase was extracted with ethyl acetate (6.0 L ⁇ 2), the combined organic phase was washed with saturated brine (15.0 L), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, the obtained crude product was added to methanol (6.5 L), water (13 L) was added, the mixture was warmed to 40°C and stirred for 10 to 48 hours, filtered and the filter cake was washed with water (2 L ⁇ 2) and dried to obtain 0.93 kg of compound 1 (yield: 71.6%).
  • This experiment was performed using Cisbio's homogeneous time-resolved fluorescence conjugate energy transfer (HTRF ® method) for activity detection.
  • enzyme, biotin-labeled peptide substrate, ATP and detection compound were mixed and incubated for reaction.
  • EDTA was added to terminate the reaction, and at the same time, Eu-labeled antibody and streptavidin-labeled XL665 were added for reaction and detection.
  • the data were represented by fluorescence signal readings at 665 nm and 620 nm respectively, with a high ratio of 665 nm / 620 nm indicating high activity and a low ratio of 665 nm / 620 nm indicating inhibition of activity.
  • Compound dilution the compound to be tested was 4-fold diluted, with a total of 10 concentrations, and the final system concentration was from 10 ⁇ M to 0.038 nM;
  • the reaction was spotted on P81 ion exchange paper (Whatman # 3698-915), the filter was washed thoroughly with 0.75% phosphoric acid, and the radiophosphorylated substrate remaining on the filter was measured.
  • Kinase activity data were expressed as a percentage of kinase activity in the test sample compared to the vehicle (DMSO) reaction.
  • IC 50 and curve fitting can be obtained by Graphpad software Prism4.
  • Table 1 Table 1 IC 50 value of compound of formula (I) for inhibition of TrkA enzyme Compound number TrkA IC 50 (nM) Compounds of formula (I) 6.64
  • test compound standard inhibitor (100 x final concentration) and mixed substrate working solution were prepared; the microsome frozen in -80°C refrigerator was taken out and thawed. 2 ⁇ L of the compound to be tested and standard inhibitor solution were added to the corresponding wells, and at the same time, 2 ⁇ L of the corresponding solvent was added to the non-inhibitor control wells (NIC) and the blank control wells; secondly, 20 ⁇ L of mixed substrate solution was added to the corresponding wells except the blank wells (20 ⁇ L of Pb was added to the blank wells); human liver microsome solution was prepared (the solution was put back in the refrigerator immediately after using and marking the date), and then 158 ⁇ L of human liver microsome solution was added to all wells; the sample plate was put in a 37 °C water bath for pre-incubation, and then a coenzyme factor (NADPH) solution was prepared; after 10 minutes, 20 ⁇ L of NADPH solution was added to all wells, the sample plate was shaken well, and in
  • Standard protocols were used to test the pharmacokinetic characteristics of the tested compounds in rodents after intravenous injection and oral administration, in the experiment, the tested compounds were prepared into a clear solution or a homogeneous suspension, and the rats were given a single intravenous injection and oral administration.
  • the solvent was a certain proportion of ethanol and normal saline solution or a certain proportion of HP- ⁇ cyclodextrin solution of dimethyl sulfoxide (the pH was adjusted 3 to 4), the mixture was vortex-stirred to prepare 1 mg/mL clear solution and filtered by a microporous membrane for later use; oral solvent was a certain proportion of sodium carboxymethyl cellulose solution or a certain proportion of HP- ⁇ cyclodextrin solution of dimethyl sulfoxide (the pH was adjusted to above 4), after the compound to be tested was mixed with the solvent, the mixture was vortex-stirred to obtain a uniform suspension of 30 mg/mL for later use.
  • C 0 is the initial concentration
  • T 1/2 is the elimination half-life
  • V dss is the steady-state apparent volume of distribution
  • Cl is the total clearance
  • AUC 0-inf is area under the plasma drug concentration-time curve from 0 time to extrapolation to infinity area
  • C max is the peak concentration
  • T max is the peak time.
  • Male Beagle dogs were used as the test animals, and the plasma concentrations of the compounds were determined after a single administration and the pharmacokinetic behavior was evaluated.
  • the purpose of the experiment was to test the pharmacokinetic characteristics of the tested compounds in non-rodents after intravenous injection and oral administration, in the experiment, the tested compounds were prepared into a clear solution or a homogeneous suspension, and the beagle dogs were given a single intravenous injection or oral administration.
  • the solvent was a certain proportion of HP- ⁇ - cyclodextrin solution of dimethyl sulfoxide or a certain proportion of ethanol, and a normal saline solution of polyethylene glycol 400, vortexed and ultrasonicated to prepare a 2 mg/kg clear solution and filtered by microporous membrane for later use; oral solvent was a certain proportion of HP- ⁇ cyclodextrin solution of dimethyl sulfoxide or a certain proportion of sodium carboxymethyl cellulose solution, after the compound to be tested was mixed with the solvent, the solvent was vortexed and ultrasonicated to prepare a 3 mg/mL uniform suspension for later use.
  • Co is the initial concentration
  • T 1/2 is the elimination half-life
  • V dss is the steady-state apparent volume of distribution
  • Cl is the total clearance
  • AUC 0-inf is area under the plasma drug concentration-time curve from 0 time to extrapolation to infinity area
  • C max is the peak concentration
  • T max is the peak time.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP21738162.3A 2020-01-10 2021-01-08 Verfahren zur herstellung von pyrrolidinylharnstoffderivaten Active EP4089087B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010027384 2020-01-10
PCT/CN2021/070962 WO2021139795A1 (zh) 2020-01-10 2021-01-08 吡咯烷基脲衍生物的制备方法

Publications (3)

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EP4089087A1 true EP4089087A1 (de) 2022-11-16
EP4089087A4 EP4089087A4 (de) 2023-06-14
EP4089087B1 EP4089087B1 (de) 2024-07-03

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Country Status (5)

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US (1) US11691965B2 (de)
EP (1) EP4089087B1 (de)
JP (1) JP7337279B2 (de)
CN (1) CN114945568B (de)
WO (1) WO2021139795A1 (de)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2012256237B2 (en) * 2011-05-13 2017-01-05 Array Biopharma Inc. Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as TrkA kinase inhibitors
PL3154959T3 (pl) 2014-05-15 2019-12-31 Array Biopharma, Inc. 1-((3S,4R)-4-(3-Fluorofenylo)-1-(2-metoksyetylo)pirolidyn-3-ylo)-3-(4-metylo-3- (2- metylopirymidyn-5-ylo)-1-fenylo-1H-pirazol-5-ilo)-mocznik jako inhibitor kinazy TrkA
US10160727B2 (en) 2014-08-06 2018-12-25 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TrkA inhibitory activity
WO2016116900A1 (en) 2015-01-23 2016-07-28 Gvk Biosciences Private Limited Inhibitors of trka kinase
US10640495B2 (en) 2015-07-07 2020-05-05 Shionogi & Co., Ltd. Heterocycle derivatives having TrkA inhibitory activity
EP3412663B1 (de) * 2016-02-04 2022-09-07 Shionogi & Co., Ltd. Stickstoffhaltige heterozyklische und carbozyklische derivate mit trka-hemmender wirkung
EP3822266A4 (de) * 2018-07-12 2022-04-27 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd Pyrrolidinylharnstoffderivate und ihre verwendung bei trka-verwandten erkrankungen

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CN114945568A (zh) 2022-08-26
US11691965B2 (en) 2023-07-04
WO2021139795A1 (zh) 2021-07-15
EP4089087B1 (de) 2024-07-03
JP7337279B2 (ja) 2023-09-01
CN114945568B (zh) 2024-02-13
US20230065496A1 (en) 2023-03-02
JP2023500750A (ja) 2023-01-10
EP4089087A4 (de) 2023-06-14

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